Coated tablet formulation and method

ABSTRACT

A coated tablet formulation is provided which includes a medicament such as the DPP4-inhibitor, saxaglipitin 
                         
which is subject to intra-molecular cyclization, which formulation includes a tablet core containing one or more fillers, and other conventional excipients, which tablet core includes a coating thereon which may include two or more layers, at least one layer of which is an inner seal coat layer which is formed of one or more coating polymers, a second layer of which is formed of medicament which is the DPP4-inhibitor and one or more coating polymers, and an optional, but preferable third outer protective layer which is formed of one or more coating polymers. A method for forming the coated tablet is also provided.

FIELD OF THE INVENTION

This application is a divisional of U.S. patent application Ser. No.11/137,068, filed May 25, 2005, now U.S. Pat. No. 7,951,400, whichclaims a benefit of priority from U.S. Provisional Application No.60/575,319, filed May 28, 2004, the entire disclosure of which is hereinincorporated by reference.

The present invention relates to a coated tablet formulation whichincludes a tablet core coated with a medicament such as aDPP4-inhibitor, such as saxagliptin, and to a method for preparing suchcoated tablet formulation.

BACKGROUND OF THE INVENTION

The compound of the structure

(hereinafter the above DPP4-inhibitor or saxaglipitin) is an orallyactive reversible dipeptidyl peptidase-4 (DPP4) inhibitor, which is atherapeutic agent for treatment of Type-2 diabetes mellitus which isdisclosed in U.S. Pat. No. 6,395,767.

After a meal intake, insulinotropic hormone GLP-1 is released which inturn induces insulin release from the pancreas. Some of the GLP-1 isinactivated by the DPP4 present in plasma and intestinal capillaryendothelium. Therefore, if the DPP4 is inhibited, more GLP-1 will beavailable to activate insulin release from the pancreas. The advantageof this mechanism of insulin release is that insulin is secreted only inresponse to a meal. Therefore, problems of hypoglycemia associated withother diabetes drugs will be less likely with a DPP4 inhibitor.

The above DPP4 inhibitor is a labile compound which is prone to anintra-molecular cyclization as shown below.

The resultant degradant, cyclic amidine (mainly cis-cyclic amidine(CA)), is not therapeutically active and therefore, its formation is notdesirable. This cyclization reaction can occur both in solid state andsolution state. The rate of intra-molecular cyclization is acceleratedwhen formulations are subject to commonly used processing activitiessuch as wet granulation, roller compaction, or tabletting. In addition,most commonly used excipients, when mixed with this compound, canaccelerate the rate of cyclization. Moreover, the level of cis-cyclicamidine increases when the drug to excipient ratio increases posing morechallenges for low strength dosage forms. Given these properties of themolecule, manufacture of a conventional tablet dosage form for theDPP4-inhibitor, which is a preferred dosage form, is not a viableoption.

Currently, capsule formulations containing a dry mix of theDPP4-inhibitor and commonly used excipients are manufactured at a smallscale and used for clinical studies. The scale up of capsuleformulations containing the DPP4-inhibitor will also be problematicsince it will involve milling to control the particle size of theDPP4-inhibitor so that capsules of lower strengths are manufacturedwithout content unifomity problems.

Additionally, most of the therapeutic agents as a single entity or as acombination product for diabetes treatments are available in a tabletdosage form. Since a tablet dosage form using traditional manufacturingprocess is not feasible for the DPP4-inhibitor, its manufacturing withother therapeutic agents, as a combination tablet will be even moreproblematic.

Thus, it is seen that there is clearly a need for stable pharmaceuticalformulations containing medicaments which are subject to intra-molecularcyclization which results in formation of degradants such as cyclicamidines which are not therapeutically active.

U.S. Pat. No. 6,395,767 to Robl et al. (hereinafter Robl et al.)discloses cyclopropyl-fused pyrrolidine-based dipeptidyl peptidase IVinhibitors (DPP4 inhibitors) which include compounds having thestructure

or a pharmaceutically acceptable salt thereof, wherein thepharmaceutically acceptable salt can be the hydrochloride salt or thetrifluoroacetic acid salt.

Robl et al. discloses that the DPP4 inhibitors including those set outabove may be formulated as tablets, capsules, granules or powders.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention a coated tablet is providedwhich may include a medicament which is subject to intra-molecularcyclization, but is surprisingly stable under normal storage conditions,that is at 30° C. and 60% relative humidity.

The coated tablet of the invention includes a tablet core (also referredto as a “core”, “tablet core”, “placebo”, “placebo core tablet”, “tabletcore composition” or “core composition”) and

a) a coating layer coated on the core, which coating layer is an innerseal coat formed of at least one coating polymer;

b) a second coating layer, disposed over the inner seal coat, formed ofa medicament and at least one coating polymer which preferably is thesame coating polymer in the inner seal coat; and optionally

c) an outer protective coating layer, disposed over the second coatinglayer, formed of at least one coating polymer, which preferably is thesame coating polymer in the second coating layer and inner seal coat,but need not necessarily include the same amounts of such polymer.

The medicament will preferably be the DPP4-inhibitor of the structure

or a pharmaceutically acceptable salt thereof, such as the HCl salt,also referred to as Compound A.

In a preferred embodiment, the coated tablet of the invention willinclude a tablet core which is formed of one or more bulking agents orfillers, optionally one or more binders, optionally one or moredisintegrants, and optionally one or more tableting lubricants,

a) an inner seal coating layer which includes at least one coatingpolymer which preferably is a polyvinyl alcohol (PVA) based polymer;

b) a second coating layer disposed over the seal coating layer a) whichincludes at least one medicament and at least one coating polymer whichis preferably a PVA based polymer, and preferably the same as thecoating polymer of the inner seal coating layer.

The above coating layers are applied to the tablet core preferably byspray coating on to the tablet core.

In a more preferred embodiment of the invention, an outer protective orthird coating layer will be coated over the second coating layer(containing the medicament) and will function as a protective layer. Thethird or protective coating layer may preferably include similarcomponents as in the second coating layer except that it will notinclude a medicament, but may optionally include one or more colorants,and may not necessarily include the same amounts of such components.Optionally, a fourth layer (which includes similar components as in thethird layer) containing colorants and a coating polymer can also beapplied to differentiate tablets of various strengths. The first,second, third and fourth coating layers may be formed of the same ordifferent coating polymers.

It has been found that the coated tablets of the invention exhibitsuperior chemical stability as compared to traditional tabletsmanufactured using conventional dry granulation or wet granulationtechniques.

The coating approach will also facilitate preparation of a combinationformulation of a problematic medicament with another drug by using theother drug tablet as a starting tablet (instead of the tablet core orplacebo mentioned above) and applying the inner seal coating and thesecond coating containing the problematic medicament and coatingpolymer, and optionally but preferably, the outer protective coatingover the other drug tablet.

The coated tablets of the invention may be prepared preferably usingperforated pan coaters. Fluid bed coating and spray coating may be usedas well.

In addition, in accordance with the present invention, a method isprovided for preparing the coated tablet of the invention, which methodincludes the steps of

a) providing a tablet core;

b) coating the tablet with an inner seal coating layer formulation whichincludes at least one coating polymer;

c) drying the coated tablet to form an inner seal coating thereon;

d) coating the so-coated tablet with a second coating layer formulationwhich includes medicament and at least one coating polymer;

e) drying the so-coated tablet to form a second coating layer(containing medicament) thereon;

f) optionally, but preferably, coating the so-coated tablet with a thirdouter protective coating layer formulation which includes at least onecoating polymer; and

g) optionally, coating the so-coated tablet with a fourth outerprotective coating layer which includes at least one coating polymer andcolorant, and

h) drying the so-coated tablet to form the coated tablet of theinvention.

In a preferred embodiment of the method of the invention the inner sealcoating layer formulation, the second coating layer formulation and theouter protective coating layer(s) formulation(s) each will be applied asa suspension of the coating polymer in a coating solvent.

The third and fourth outer protective coating layers need not include amedicament (although it may, if desired), and may be formed of the othercomponents of the first coating layer and/or second coating layer. Thesecond coating layer may be formed of the components of the firstcoating layer and/or third/and or fourth coating layer, but notnecessarily the same amounts of such components.

In preparing the coated tablet of the invention, coating suspensionswhich include coating polymer in water are prepared. Other coatingsolvents which may be employed include ethanol, methanol, and isopropylalcohol, with water being preferred. Tablets which are placebos (containno medicament) and form tablet cores are coated with the inner sealcoating suspension and are dried. The second coating layer suspensioncontaining medicament and coating polymer is applied over the so-coatedtablets which are then dried.

Where the coated tablet of the invention is to include an outerprotective layer, a coating suspension is prepared as in the case of theinner seal coating suspension but without medicament. The coatingsuspension will then be coated onto the previously coated tablets asdescribed for the inner seal coating and second coating to form aprotective coating layer thereon.

The coated tablets of the invention are useful in the treatment ofmammals such as humans, dogs and cats for Type II diabetes.

DETAILED DESCRIPTION OF THE INVENTION

The tablet core or placebo employed in the coated tablet of theinvention will include conventional pharmaceutical excipients to enableformation of a pharmaceutically acceptable solid tablet core. The tabletcore may be in the form of a tablet, bead, beadlet, or pill, all of theabove being collectively referred to as a tablet core.

The coated tablet of the invention will contain medicament, such as theabove DPP4-inhibitor, saxaglipitin, in an amount within the range fromabout 0.1 to about 70% by weight and preferably from about 1 to about50% by weight of the tablet core.

The tablet core employed in the coated tablet of the invention willpreferably contain

a) at least one bulking agent or filler;

b) optionally at least one binder;

c) optionally at least one disintegrant; and

d) preferably but optionally at least one lubricant.

wherein

a) the bulking agent or filler is present in an amount within the rangefrom about 1 to about 95% by weight, preferably from about 10 to about85% by weight;

b) the binder is present in an amount within the range from about 0 toabout 20% by weight, preferably from about 1 to about 10% by weight;

c) the disintegrant is present in an amount within the range from about0 to about 20% by weight, and preferably from about 0.25 to about 10% byweight; and

d) the lubricant is present in an amount within the range from about 0to about 5% by weight, preferably from about 0.2 to about 2% by weight,all of the above % by weight being based on the weight of the tabletcore.

It is preferred that the bulking agents are microcrystalline celluloseand lactose monohydrate;

the disintegrant is croscarmellose sodium; and

the lubricant is magnesium stearate.

The tablet cores present in the coated tablets of this invention can beprepared by a variety of processes and order of addition of excipients.The utility of these formulations is not limited to a specific dosageform or manufacturing process. Tablet cores may be manufactured by wetgranulation, dry granulation, direct blending or any otherpharmaceutically acceptable process.

In accordance with the present invention, a preferred method is providedfor preparing the tablet cores employed in the coated tablets of theinvention which includes the steps of blending the one or moreexcipients such as bulking agent, optionally binder and optionallydisintegrant. A lubricant will be preferably added to the blend tofacilitate tablet formation.

The bulking agents or fillers will be present in the tablet corecompositions of the invention in an amount within the range from about 1to about 95% by weight and preferably from about 10 to about 85% byweight of the core composition. Examples of bulking agents or fillerssuitable for use herein include, but are not limited to, cellulosederivatives such as microcrystalline cellulose or wood cellulose,lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol,fructose, xylitol, sorbitol, corn starch, modified corn starch,inorganic salts such as calcium carbonate, calcium phosphate, dicalciumphosphate, calcium sulfate, dextrin/dextrates, maltodextrin,compressible sugars, and other known bulking agents or fillers, and/ormixtures of two or more thereof, preferably microcrystalline cellulose.

The binder will be optionally present in the pharmaceutical compositionsof the invention in an amount within the range from about 0 to about 20%weight, preferably from about 1 to about 10% by weight of the corecomposition. Examples of binders suitable for use herein include, butare not limited to, hydroxypropyl cellulose, corn starch, pregelatinizedstarch, modified corn starch, polyvinyl pyrrolidone (PVP) (molecularweight ranging from about 5,000 to about 1,000,000, preferably about40,000), hydroxypropyl methylcellulose (HPMC), lactose, gum acacia,ethyl cellulose, cellulose acetate, as well as a wax binder such ascarnauba wax, paraffin, spermaceti, polyethylenes or microcrystallinewax, as well as other conventional binding agent and/or mixtures by twoor more thereof, preferably hydroxypropyl cellulose.

The disintegrant will be optionally present in the pharmaceuticalcomposition of the invention in an amount within the range from about 0to about 20% by weight, preferably from about 0.25 to about 10% byweight of the core composition. Examples of disintegrants suitable foruse herein include, but are not limited to, croscarmellose sodium,crospovidone, starch, potato starch, pregelatinized starch, corn starch,sodium starch glycolate, microcrystalline cellulose, low substitutedhydroxypropyl cellulose or other known disintegrant, preferablycroscarmellose sodium.

The lubricant will be optimally present in the pharmaceuticalcomposition of the invention in an amount within the range from about0.1 to about 5% by weight, preferably from about 0.2 to about 2% byweight of the core composition. Examples of tableting lubricantssuitable for use herein include, but are not limited to, magnesiumstearate, zinc stearate, calcium stearate, talc, carnauba wax, stearicacid, palmitic acid, sodium stearyl fumarate or hydrogenated vegetableoils and fats, or other known tableting lubricants, and/or mixtures oftwo or more thereof, preferably magnesium stearate.

The inner seal coating layer formulation (also referred to as the firstcoating layer) will include up to 95% of polymer based on the weight ofthe inner seal coating layer, and may be prepared as describedhereinbefore. The formulation will contain at least one coating layerpolymer and a coating solvent as described above, which preferably iswater, which is used for processing and removed by drying. The coatinglayer polymer may be hydroxypropyl methylcellulose, polyvinyl alcohol(PVA), ethyl cellulose, methacrylic polymers or hydroxypropyl cellulose,preferably PVA. The coating layer may also optionally include aplasticizer such as triacetin, diethyl phthalate, tributyl sebacate orpolyethylene glycol (PEG), preferably PEG; and an anti-adherent orglidant such as talc, fumed silica or magnesium stearate, opacifyingagent such as titanium dioxide. The coating layer may also include ironoxide based colorants. The coating material is commercially availableunder the trade name Opadry® HP or Opadry® II white.

The second coating layer formulation will preferably be similar incomposition to the first coating layer formulation although it willinclude medicament, preferably the DPP4-inhibitor in an amount withinthe range from about 0.5 to about 70%, preferably from about 30 to about50% by weight, based on the weight of the second coating layer.

The third outer protective coating layer will preferably be similar incomposition to the first coating layer.

The fourth coating layer where present will preferably be similar incomposition to the third outer protective coating layer and will includecolorant as desired, such as within the range from about 0.5 to about5.0% by weight, based on the weight of the fourth coating layer.

The inner seal coating layer will preferably be formed of coating layerpolymer in an amount within the range from about 10 to about 95%,preferably from about 20 to about 90% by weight of the inner sealcoating layer, optionally plasticizer in an amount within the range fromabout 10 to about 30%, preferably from about 15 to about 20% by weightof the coating layer, and anti-adherent or glidant in an amount withinthe range for about 15 to about 30%, preferably from about 10 to about15% by weight of the inner seal coating layer.

The second coating layer will be preferably formed of coating layerpolymer in an amount within the range from about 30 to about 99.5%,preferably from about 40 to about 60% by weight of the second coatinglayer and medicament in an amount within the range from about 0.25% toabout 70%, preferably from about 20 to about 50% by weight of the secondcoating layer.

The coating layer polymer in the second coating layer will be at leastabout 5 mg with a 200 mg tablet core, and the medicament will be atleast about 0.5 mg.

The third outer protective coating layer will preferably be of similarcomposition to the first coating layer.

The inner seal coating layer will be present in an amount within therange from about 1 to about 5%, preferably from about 1 to about 3% byweight of the finished coated tablet; the second coating layer(containing medicament) will be present in an amount within the rangefrom about 0.25 to about 70%, preferably from about 1 to about 50% byweight of the finished coated tablet, depending on potency; and thethird outer protective coating layer and fourth layer where present willeach be present in an amount within the range from about 1 to about 10%,preferably from about 1 to about 5% by weight of the finished coatedtablet.

Preferred coated tablet formulations in accordance with the inventionare set out below.

Possible Range %/ Preferred Range Material mg by weight of 200 mg %/mgby weight of 200 mg Tablet Placebo placebo core tablet placebo coretablet Bulking Agent   2 to 95%/4 to 190 mg   10 to 85%/20 to 170 mgLactose   0 to 95%/0 to 190 mg   20 to 75%/40 to 150 mg Microcrystalline  0 to 95%/0 to 190 mg   20 to 75%/40 to 150 mg cellulose Disintegrant  0 to 20%/0 to 40 mg 0.25 to 10%/0.5 to 20 mg Croscarmellose   0 to20%/0 to 40 mg   2 to 10%/4 to 20 mg sodium Lubricant 0.1 to 5%/0.2 to10 mg  0.2 to 2%/0.4 to 4 mg Magnesium 0.1 to 5%/0.2 to 10 mg  0.2 to2%/0.4 to 4 mg Stearate

%/mg by weight First Inner %/mg by weight of 200 mg of 200 mg SealCoating Layer placebo core tablet placebo core tablet Coating polymer,and 0.5 to 50%/1 to 100 mg 1 to 3%/2 to 6 mg optional plasticizer andglidants

%/mg by weight %/mg by weight of 200 mg of 200 mg Second Coating Layerplacebo core tablet placebo core tablet DPP4-inhibitor 0.1 to 70%/0.2 to140 mg 1 to 50%/2 to 100 mg (free base or HCl salt) Coating polymer, and  1 to 70%/2 to 140 mg 1 to 50%/2 to 100 mg optional plasticizer andglidants

%/ %/mg Third Outer Protective mg by weight of 200 mg by weight of 200mg Coating Layer placebo core tablet placebo core tablet Coatingpolymer, and 0.5 to 50%/1 to 100 mg 1 to 5%/2 to 10 mg optionalplasticizer, glidants and color

The following working Example represents a preferred embodiment of theinvention.

EXAMPLE

A 500 g batch of 2.5 mg DPP4 coated tablets having the followingcomposition were prepared as described below

Weight (mg) % by weight of a 200 mg Tablet Core placebo core tabletLactose Monohydrate NF 99 mg (49.5%) Microcrystalline Cellulose NF 90 mg(45%) Croscarmellose Sodium NF 10 mg (5%) Magnesium Stearate NF 1 mg(0.5%) Total 200 mg (100.0%) Inner Seal Coating Layer 4 mg (2%) Opadry ®HP which contains the following ingredients Polyvinyl Alcohol 40% PEG20% Talc 15% Titanium dioxide 25% Middle Layer DPP4-inhibitor,Saxaglipitin 2.5 mg (1.25%) Opadry ® HP 20 mg (10%) Outer ProtectiveLayer Opadry ® HP 4 mg (2%)

The 500 g of tablet cores were prepared as follows.

Lactose monohydrate, croscarmellose sodium, and microcrystallinecellulose were blended in a planetary mixer. The blend was thenlubricated by blending with pre-screened magnesium stearate using aTurbula mixer. The lubricated blend was compressed using a singlestation press or using a rotary press into 200 mg placebo tablets.

Inner Seal Coating Layer

The inner seal coating suspension was prepared as follows.

0.1 N HCl (about 226.7 g) in a metal container was continuously stirredwith a lightening mixer. 40 g Opadry® HP powder was quickly added intothe vortex. After the powder addition was completed, mixing wascontinued at a low speed until a uniform mixture was visually evident.pH of the resulting suspension was measured and pH was adjusted to 2using concentrated HCl or NaOH.

A Glatt coater was set up according to the following parameters

Glatt Coater Parameter

Pump rate 3.5-5 ml/min Pan speed 20 rpm Air pressure 1.5 bar Inlet airtemperature 50° C. Exhaust air temperature about 38° C. Air flow 80m³/hour Gun to bed distance 6.5 inch Nozzle size 0.8 mm

The tablet cores were preheated in a coating pan for about 10 to 15minutes. 30 heated tablets were weighed. Drying of the tablets wascontinued until the moisture was driven out of the tablet and tabletweight became constant. The final weight of 30 tablets was designed asA.

The 30 tablets were coated with the inner seal coating suspension asprepared above employing the Glatt coater.

The 30 tablets were weighed every 10 minutes (and the weight recorded)until the tablet weight reached the targeted weight (Equation 1). Thecoated tablets were dried by heating until the tablet weight becameconstant. The final weight of the so-coated tablets was designated as B.Targeted weight=A×1.02=B  Equation 1Middle (Drug) Coating Layer

The middle drug-containing coating layer suspension was prepared asfollows.

12.5 g of the DPP4-inhibitor (free base) was added to 1000 ml of 0.1 NHCl in a metal container. The pH was measured and adjusted to 2. The HClwas continuously stirred and 100 g Opadry® HP was quickly added into thevortex. The mixture was then stirred at low speed until a uniformmixture was visually evident. The pH of the suspension was maintained at2 using either concentrated HCl or 1N HCl as necessary.

The seal coated tablet cores prepared above were coated with the coatingsuspension containing the DPP4-inhibitor prepared above employing theGlatt coater. The 30 seal coated tablets were weighed, initially every30 minutes, then every 15 minutes and the weight recorded until thetargeted weight was reached (Equation 2). The so-coated tablets weredried by heating until the tablet weight became constant. The finalweight of 30 tablets was designated as C.Targeted weight=B+30×(2.925(equivalent to 2.5mg freebase)+20mg)=B+687.75mg=C  Equation 2

The amount of drug coated onto the tablets was determined using HPLC,fiber optic probe, or NIR or other suitable means. Coating was stoppedwhen the targeted amount of drug was deposited.

Outer Protective Coating Layer

The so-coated tablets were then coated with a suspension of Opadry® HPas used in forming the inner seal coating. The 30 tablets were weighedevery 10 minutes and the weight recorded until tablet weight reached thetargeted weight (Equation 3). The tablets were dried by heating untilthe tablet weight became constant.

The final weight of 30 tablets was designed as D.Targeted weight=C+30×4mg=C+120mg=D  Equation 2

The so-coated tablets were transferred to a suitable container.

The tablets of the invention so-prepared had superior stability toconventional tablet formulations (wherein the drug was in the core) andcapsule formulations.

The above 2.5 mg potency coated tablets of the invention were stored atvarious storage conditions up to and including 41 weeks and stabilitydata related to presence of the degradant cyclic amidine (mainlycis-cyclic amidine (Cis-CA)) were collected. As shown in Table 1 set outbelow, no cis-CA was detected at 25° C./60% RH storage condition. Thecis-CA levels were 0.22% and 0.32% at 30° C./60% RH and 40° C./75% RHstorage conditions, respectively. These levels are significantly lowerthan those observed in the 5 mg and 20 mg potency capsule formulationsshown in Table 2.

TABLE 1 Twenty-six weeks stability data on 2.5 mg potency tablets coatedwith Opadry ® HP, free base as starting material, and three coatinglayers. For stability evaluation, tablets were packaged in HDPE bottles.4 wks for all closed 8 wks for all closed conditions conditions 2 wksfor all closed 1 wk for two open 5 wks for two open conditionsconditions conditions Cis- Trans- Cis- Trans- Cis- Trans- StorageCondition Amide % CA % CA % Amide % CA % CA % Amide % CA % CA %  5°C.-closed 0 0 0 0 0 0 0 0 0 25° C./60% RH-closed 0 0 0 0 0 0 0 0 0 30°C./60% RH-closed 0 0 0 0 0 0 0 0 0 40° C./75% RH-closed 0 0 0 0 0.05 0 00.09 0 50° C.-closed 0 0.17 0 0 0.33 0.15 0 0.52 0.12 30° C./60% RH-openNA NA NA 0 0 0 0 0.20 0.06 40° C./75% RH-open NA NA NA 0 0.68 0.15 03.22 0.42 12 wks for all closed 26 wks for all closed 41 wks for allclosed conditions conditions conditions Cis- Trans- Cis- Trans- Cis-Trans- Storage Condition Amide % CA % CA % Amide % CA % CA % Amide % CA% CA % 5° C.-closed 0 0 0 0 0 0 0 0 0 25° C./60% RH-closed 0 0 0 0 0 00.03 0 0 30° C./60% RH-closed 0 0 0 0 0.22 0 0.03 0.17 0 40° C./75%RH-closed 0 0.20 0.05 0 0.32 0 0.03 0.90 0 50° C.-closed 0 0.75 0.15 01.00 0 0 1.62 0 30° C./60% RH-open NA NA NA NA NA NA NA NA NA 40° C./75%RH-open NA NA NA NA NA NA NA NA NA NA denotes “data not available”

TABLE 2 Stability data for capsule formulations (benzoate salt of DPP44.8%, Anhydrous lactose 50.2%, lactose hydrous 40%, croscarmellosesodium 2%, and sodium stearyl fumarate 3%, fill weights for 5 mg and 20mg capsules are 150 mg and 350 mg, respectively.) 5 mg capsule 20 mgcapsule 2 wks 4 wks 13 wks 26 wks 2 wks 4 wks 13 wks 26 wks ConditionsCis-CA % Cis-CA % Cis-CA % Cis-CA % Cis-CA % Cis-CA % Cis-CA % Cis-CA %25° C./60% RH-closed 0.11 0.13 0.20 0.31 0.08 0.05 0.14 0.26 40° C./75%RH-closed 0.23 0.35 0.61 0.95 0.22 0.26 0.46 0.62 50° C.-closed NA 0.731.72 NA NA 0.43 1.19 NA

What is claimed is:
 1. A combination formulation comprising a) a drugtablet; b) an inner seal coating layer coated on the drug tablet,wherein the inner seal coating layer comprises about 1 mg to about 100mg of a coating polymer formulation comprising a polyvinyl alcohol; andc) a second coating layer coated on the inner seal coating layer of thedrug tablet, wherein the second coating layer comprises about 0.2 mg toabout 140 mg saxagliptin

or a pharmaceutically acceptable salt thereof and about 2 mg to about140 mg of a coating polymer formulation comprising a polyvinyl alcohol;and d) an outer protective coating layer coated on the second coatinglayer of the drug tablet, wherein the outer protective coating layercomprises about 1 mg to about 100 mg of a coating polymer formulationcomprising a polyvinyl alcohol; wherein the drug tablet is other thansaxagliptin or a pharmaceutically acceptable salt thereof.
 2. Thecombination formulation as defined in claim 1, wherein said secondcoating layer is comprised of from about 0.1 to about 70% by weightsaxagliptin or a pharmaceutically acceptable salt thereof and from about30 to about 99.5% by weight coating polymer formulation, based on theweight of the second coating layer.
 3. The combination formulation asdefined in claim 1, wherein the coating polymer formulation in thesecond coating layer is at least about 2 mg with a 200 mg drug tablet,and the saxagliptin or a pharmaceutically acceptable salt thereof is atleast about 0.2 mg.
 4. The combination formulation as defined in claim1, wherein the saxagliptin is present as its hydrochloride salt.
 5. Thecombination formulation as defined in claim 1, wherein the inner sealcoating layer further comprises polyethylene glycol.
 6. The combinationformulation as defined in claim 1, wherein the inner seal coating layercomprises about 40% polyvinyl alcohol, and further comprises about 20%polyethylene glycol, about 15% talc, and about 25% titanium dioxide. 7.The combination formulation as defined in claim 1, wherein the coatingpolymer formulation of the second coating layer further comprisespolyethylene glycol.
 8. The combination formulation as defined in claim1, wherein the coating polymer formulation of the second coating layercomprises about 40% polyvinyl alcohol, and further comprises about 20%polyethylene glycol, about 15% talc, and about 25% titanium dioxide. 9.The combination formulation as defined in claim 1, wherein the outerprotective coating layer further comprises polyethylene glycol.
 10. Thecombination formulation as defined in claim 1, wherein the outerprotective coating layer comprises about 40% polyvinyl alcohol, andfurther comprises about 20% polyethylene glycol, about 15% talc, andabout 25% titanium dioxide.
 11. The combination formulation as definedin claim 1, wherein the inner seal coating layer consists essentially ofthe coating polymer formulation in an amount in the range of 2 mg to 6mg; the second coating layer consists essentially of the saxagliptin infree base or HCl salt form in an amount in the range of 0.5 mg to 140mg, and the coating polymer formulation in an amount in the range of 2mg to 100 mg; and the outer protective coating layer consistsessentially of the coating polymer formulation in an amount in the rangeof 2 mg to 10 mg.